Cyclopentanophenanthrene compounds and method for preparation thereof



United States Patent CYCLOPENTANOPHENANTHRENE COMPOUNDS AND METHOD FORPREPARATION THEREOF No Drawing. Application September 22, 1952, SerialNo. 310,934

Claims priority, application Mexico October 8, 1951 3 Claims. (Cl.260-3973) The, present invention relates to cyclopentanophenanthrenecompounds and to a novel method for the preparation thereof. Moreparticularly, the present invention relates to a method for thepreparation of allopregnan-3,11,20-trione by degradation of22-isoallospirostan- 3,11-dione.

Allopregnan-3,l1,20-trione was first obtained and described by Steigerand Reichstein (Helv. Chim. Acta, 21,161 (1938)), who prepared thiscompound by degradation o'f corticosterone. Since this last-mentionedcompound possesses a keto group in position 11 of the molecule, itrepresents a potentially valuable intermediate for the synthesis ofcortisone and the present method which producesallopregnan-3,l1,20-trione, therefore, provides a new path for thesynthesis of cortisone.

In United States patent application Serial Number 306,512 of Djerassiand Rosenkranz, filed August 26, 1952, a method is disclosed for thepreparation of 22- isoallospirostan-3,ll-dione by the oxidation of35,110- dihydroxy sapogenins.

In accordance with the present invention, it has been discovered thatthis last-mentioned compound,- upon treatment with acetic anhydrideunder pressure, at approximately 200" C., can be converted into thecorresponding A -allo-furostene-26-ol-3,1l-dione acetate. It has furtherbeen discovered in accordance with the present invention, that oxidationwith chromic acid of this last-mentioned compound produces A-allopregnene- 3,11,20-trione, which can be catalytically hydrogenatedto ice In the above equation AC represents the residue acetic acid.

In practicing the reactions above set forth, the sapogenin, i. e.22-isoallospirostan-3,1l-dione, in acetic anhydride is heated in asealed tube at a temperature of approximately 200 C. for a substantialperiod of time, as for example eight hours, and is thereafter pouredinto water. The reaction mixture is then extracted with a suitableorganic solvent such as ether and the ether layer is purified as bywashing with water, sodium carbonate and again with water until neutral.Thereafter the ether solution is dried over as for example sodiumsulfate and evaporated to dryness leaving the A ?-allo-furostene26-ol-3,11-dione acetate .in the form of a yellow oil. This oil may beutilized without further purification for oxida-. tion with chromicanhydride. For this purpose, the yel= low oil may be dissolved in aceticacid with heating or in a mixture of acetic acid ethylene dichloride andwater. In either case the solution is cooled to below room tem}perature, as for example 15 C. and treated dropwise with a solution ofchromic anhydride in water and acetic acid. The reaction mixture is thenallowed to stand at room temperature for a short period of time, as forexample two hours, and then poured into water. If ethylene dichloride isutilized, the ethylene dichloride layer is then separated bydecantation. The aqueous layer is then extracted with a suitable solventsuch as chloroform, and where ethylene dichloride is utilized, thechloroform and ethylene dichloride extract are combined, washed withwater, dried and evaporated to dryness. The residue is then preferablydissolved in a solvent such as benzene and hexane and chromatographed inan alumina column. The fractions eluted with benzene are then combinedand evaporated to dryness. was A -allopregnene-3,11,20-trione.

The A -a1lopregnene-3,11,20-trione is then dissolved in ethyl acetateand shaken at room temperature and atmospheric pressure in a hydrogenatmosphere in the presence of q a suitable hydrogenation catalyst suchas palladium on barium sulfate until the absorption of-hydrogen ceased.Upon filtration of the catalyst, evaporation to dryness andcrystallization, allopregnan-3,ll,20-trione was produced.

The following specific examples will serve to illustrate but are notintended to limit the present invention: g1veallopregnan-3,l1,20-tr10ne.

The following equation serves to illustrate the present Example Iinvention: Y A solution of 5 g. of 22-isoallospirostan-3,1l-dione OH: ws-om-onl-on o GHQ-0A0 o AC0 I Acetic Anhydrlde I 0 0 l 200 0. AC K it IiOhromle Anhydride Alumina Hydrolysis OH: (3H1 0=0 =0 0- HydrogenationAfter crystallization the product (nieltingpoint' 236-238 C.) in 20 cc.acetic anhydride I was heated in a sealed tube at 196 C. during eighthours and then poured in water. The mixture was extracted with ether andthe ether layer was washed with Water, sodiurn'bicarbonate and wateruntil neutral, dried over sodium sulphate and evaporated to dryness,leaving 4.3 g. of A -allo-furostene-26-ol-3,1l-dione acetate, in theform of a yellow oil. Without further purification, this oil wasdissolved in a mixture of 45 cc. of acetic acid, 35 cc. of ethylenedichloride and 15 cc. of water and heated until all the product had goneinto solution. The solution was cooled to 15 C. and treated drop by dropwith a solution of 1.4g. of chromic anhydride in 2.1 cc. of water and 21cc. of' acetic acid. After 2 hours standing at room temperature, themixture was poured'in water and the layer of ethylene dichloride wasseparated by decantation. The aqueous layer was extracted withchloroform and the combined chloroform and ethylene dichloride extractwas washed several times with water, dried over sodium sulfate andevaporated to dryness. The residue was dissolved in a mixture of 50 cc.of benzene and 200 cc. of hexane and chromatographed in a column with150 g. of alumina. The fractions eluted with benzene were-combined andevaporated to dryness. The residue crystallized on digesting withether-pentane to give 1.6 g.- of A -allopregnene-3,11,20-trione.

Example II 5 g. of 22-isoallospirostan-3,1l-dione were treated inexactly the same Way as described in Example I. A residue of 4.27 g. ofA -allofurostene-26-0l-3,1l-dione acetate was obtained. The product wasdissolved in 60 cc. of hot acetic acid and then cooled to 15 C. Aftertreatment with 1.4 of chromic anhydride in exactly the same way asdescribed'in Example I, 1.52 g. of A -allopregnene- 3,11,20-trione wereobtained, identical with the one obtained according to Example I.

Example III A solution of 1.5 g. of A -allopregnene-3,11,20-trione in250 cc. of ethyl acetate was shaken at room temperature and atmosphericpressure in an atmosphere of hydrogen with 250 mg. of 10% palladium onbarium sulfate catalyst until the absorption of hydrogen ceased. Thispoint was reached after approximately 50 minutes. The catalyst wasfiltered and the solution was evaporated to dryness. The residuecrystallized from hexane-acetone to yield 1.29 g. ofallpregnan-3,11,20-trione, melting point 212-214" C. The product showedno selective absorption in the ultraviolet spectrum.

Although the foregoing examples and method have been illustrated withcompounds of the -allo type, the

present reaction is equally applicable to compounds of the S-normaltype. And where in the subsequent claims the term spirostan, furosteneand/ or pregnene and/or pregnane is utilized, these terms include eitherthe normal or allo compounds.

We claim:

1. A method for the preparation of pregnane-3,11,20- trione compounds,which comprises treating spirostan- 3,11-dione compounds with aceticanhydride under pressure and at a temperature of approximately 200 C.,thereafter oxidizing the A -furostene-26-ol-3,1l-dione acetate formedwith chromic anhydride followed by hydrolysis with alumina to producethe corresponding A pregnene compound, and thereafter hydrogcnating theA -pregnene-3,11,2O-trione in the presence of a palladium hydrogenationcatalyst.

2. The method of claim 1 wherein the spirostan-3,1ldione compound is22-isoallospirostan3,1l-dione and the final product isallopregnan-3,11,20-trione.

3. A process for the production of A -allopregnenc- 3,11,20-trione whichcompnses oxidizing with chromic anhydride followed by hydrolysis withalumina A al1ofurostene-26-ol-3,1l-dione acetate.

References Cited in the file of this patent UNITED STATES PATENTS2,352,852 Marker July 4, 1944 2,395,338 Marker Feb. 19, 1946 2,408,828Wagner Oct. 6, 1946 OTHER REFERENCES Marker: JACS, vol. 69, pp. 2167-73(1947). Chamberlain: JACS, August 1951, vol. 73, pp. 2396- 97, recd Apr.26, 1951.

1. A METHOD FOR THE PREPARATION OF PREGNANE-3,11-20TRIONE COMPOUNDSWHICH COMPRISES TREATING SPIROSTAN3,11-DIONE COMPOUNDS WITH ACETICANHYDRIDE UNDER PRESSURE AND AT A TEMPERATURE OF APPROXIMATELY 200* CC.,THEREAFTER OXIDIZING THE $20(22)-FUROSTENS-26-OL-3,11-DINE ACETATEFORMED WITH CHROMIC ANHYDRIDE FOLLOWED BY HYDROLYSIS WITH ALUMINA TOPRODUCE THE CORRESPONDING $16PREGNENE COMPOUND, AND THEREAFTERHYDROGENATING THE $16-PREGNENE-3,11,20-TRIONE IN THE PRESENCE OF APALLADIUM HYDROGENATION CATALYST.